Cannabis preparations in the form of marihuana, hashish, etc. have been known and used for many years for their psychoactive and therapeutic properties. The major active constituent of the resin which is exuded by the female plants of Cannabis sativa L. is (-)-6a, 10a-trans-1-hydroxy--trans-1-hydroxy-3-n-pentyl-6,6,9-trimethyl-6a,7,8,10a -tetrahydrodibenzo[b,d]pyran, also known as (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol or .DELTA..sup.9 -THC. The structure and absolute configuration of this material was first reported by Gaoni et al. in J. Amer. Chem. Soc., 86, 1946 (1964). Since that time considerable research has been directed towards the preparation of this compound via a synthetic method, thereby eliminating the need to obtain the material by extraction from natural sources.
Because of the widespread use of Cannabis preparations all over the world, it has become necessary to study the pharmacology and toxicity of the active constituent, viz. .DELTA..sup.9 -THC in greater detail. In the past, attempts to study the pharmacological effects of this compound have been hampered by variations in the potency of the plant material. Accordingly, a supply of pure synthetic material is essential to carry out these studies as well as to enable accurately reproducible dosages of the active ingredient to be used for its pharmacological properties.
One synthetic method of preparing .DELTA..sup.9 -THC is disclosed by Petrzilka in U.S. Pat. Nos. 3,560,528 and 3,668,224 and Petrzilka et al. in Helv. Chim. Acta, 52, 1102 (1969). The method of Petrzilka condenses (+)-p-mentha-2,8-dien-1-ol and olivetol in the presence of an acid to give (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol which is converted by a two-step process into the desired (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol. The Petrzilka process can be represented as follows: ##STR1##
In Helv. Chim. Acta, 52, 1102 (1969), Petrzilka et al. have postulated the intermediacy of (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol in the condensation reaction. They suggested that (+)-p-mentha-2,8-dien-1-ol and olivetol react to give (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol, but the double bond is quickly isomerized to the more thermodynamically stable position in (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol. Using a variety of acids, including boron trifluoride etherate in ether at room temperature and boron trifluoride etherate in benzene at 65.degree.-70.degree. C. for 3 hours, they obtained (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol but none of the .DELTA..sup.9 isomer. In one case where 0.0005 N hydrogen chloride in refluxing ethanol was used, a small amount (1%) of .DELTA..sup.9 -THC was obtained accompanied by 2.4% of .DELTA..sup.8 -THC and 79% of unreacted starting material (Helv. Chim. Acta, 52, p. 1124).
The (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol formed during the condensation reaction is separated from unwanted side-products by column chromatography. Treatment of the purified .DELTA..sup.8 -THC with hydrogen chloride in the presence of zinc chloride gives the chloro compound which is isolated and subsequently treated with potassium tert-amylate to yield the desired (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol. If high purity (&gt;95% pure by gas-liquid chromatography) .DELTA..sup.9 -THC is desired, the product must be purified by column chromatography and may also be distilled (Razdan et al., Experientia, 28, 121 (1972)).
Another synthesis of .DELTA..sup.9 -THC has been reported by Mechoulam et al. in J. Amer. Chem. Soc., 94,6159 (1972). The Mechoulam synthesis first reacts (-)-verbenol with olivetol in the presence of boron trifluoride etherate or p-toluenesulfonic acid followed by boron trifluoride etherate to form (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol. The reaction can be represented as follows: ##STR2## The (-)-6a,10 a-trans-.DELTA..sup.8 -tetrahydrocannabinol is then transformed to (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol by the addition of hydrogen chloride and subsequent elimination using potassium tert-amylate. Thus, both the Mechoulam and Petrzilka methods require three steps and involve at least two careful chromatographic separations to obtain (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol of high purity.
A single step synthesis of a cis and trans mixture of (-)-.DELTA..sup.9 -tetrahydrocannabinol has been reported by Razdan and Handrick in U.S. Pat. No. 3,734,930 and Razdan and Handrick in J. Amer. Chem. Soc., 92, 6061 (1970). The synthesis is achieved by reacting (+)-trans-2-carene oxide and olivetol in the presence of boron trifluoride etherate or p-toluenesulfonic acid as represented below: ##STR3##
This synthesis avoids the problem of isomerization of the double bond to the .DELTA..sup.8 position but gives both the cis and trans isomers of (-)-.DELTA..sup.9 -tetrahydrocannabinol as the major reaction products. Separation of the cis and trans isomers is difficult. Techniques such as preparative gas-liquid chromatography or high pressure-liquid chromatography must be employed to separate the isomers. Utilization of these techniques for preparation of large amounts of material is considered impractical at the present time. Thus, the carene oxide synthesis is limited to preparation of small quantities of (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol.
Of the three syntheses of .DELTA..sup.9 -THC described above, the Petrzilka and Mechoulam methods require three steps and two chromatographic separations. The Razdan synthesis from (+)-trans-2-carene oxide provides a mixture of cis and trans (-)-.DELTA..sup.9 -tetrahydrocannabinol in one step but separation of the trans from the cis is difficult. Based on the availability of starting materials and ease of separation, the Petrzilka process has been up to the present time the method of choice for preparation of (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol.
The present invention provides an improved method of preparing (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol, more particularly a one-step process for the preparation of (-)-6a,10 a-trans-.DELTA..sup.9 -tetrahydrocannabinol and related (-)-6a,10 a-trans-1-hydroxy-6,6,9-trimethyl-6a,7,8,10 a-tetrahydrodibenzo[b,d]pyrans wherein the desired compounds are obtained in good yield and can be easily purified by simple column chromatography. It also provides an improved method for making cannabidiols and related 2- and 4-(p-mentha-1,8-dien-3-yl)resorcinols.